基于兄弟姐妹配对设计和前瞻性孕产妇队列的高温暴露与早产风险关联及影响机制研究

孕产妇是气候变化风险下的敏感脆弱人群，孕期高温暴露会通过不同机制路径影响早产的风险。既往研究主要基于出生登记数据开展回顾性分析，未能控制家庭遗传和环境等聚集性因素的影响，且高温与空气污染共同暴露是否存在交互作用而加剧早产的风险仍不清楚。目前缺乏高温影响早产的机制研究，尚不明确高温是通过何种机制路径导致不同类型早产的风险。. 本项目首先基于多中心的全人群孕产妇队列，通过兄弟姐妹配对设计消除家庭因素的影响，评估孕期高温暴露对不同类型早产的效应，并揭示高温效应的区域差异及影响因素，明确高温与空气污染共同暴露的交互作用。然后通过前瞻性的孕产妇精细队列，阐明高温暴露导致不同类型早产风险的影响机制和关键路径。研究将为我国在大气环境与早产风险的关联和影响机制方面提供人群研究的关键证据，为今后开展孕期高温健康防护提供科学支撑，并为加强气象、环保、气候变化和公共卫生等领域的交叉与合作奠定基础。

Preterm birth (PTB) and its complications are the leading cause of death among newborns and children under 5 years old, leading to a heavy public health burden to the family and society. There are many risk factors for PTB, and evidence from both experimental and population studies have suggested that maternal exposure to extreme heat may increase the risk of PTB. Previous experimental studies suggested that exposure to heat may induce dehydration and the secretion of cytokines, which could decrease uterine blood flow, induce the uterine contraction and onset of labor. In addition, according to the causes of labor onset, PTB can be classified as medically indicated preterm birth (M-PTB), preterm premature rupture of membranes (PROM-PTB), and spontaneous preterm birth (S-PTB). The risk factors vary with the subtypes. Severe complications such as gestational hypertension are usually an important cause of M-PTB, while infection is known as the main cause of PROM-PTB, and changes in hormone levels related to labor may be responsible for S-PTB. However, the underlying mechanisms between heat exposure and subtypes of PTB risk remain unclear. Although previous population studies reported that maternal heat exposure was associated with PTB, most were conducted in single locations with ecological time-series analysis or retrospective cohort study design mainly based on birth registration data, without adjusting for important family clustering factors. The causal association between heat exposure and PTB remains poorly studied, and some important factors affecting the effect of regional differences should be clarified. Moreover, humans are inevitably exposed to both air pollution and extreme heat in the same atmospheric environment. Extreme heat may interact with air pollution to cause complex adverse effects on human health, but relevant evidence of synergetic effect on the risk of PTB is still limited. . To investigate the causal association and potential mechanisms between maternal heat exposure and the risk of PTB, we aim to conduct a population-based multi-center prospective cohort and sibling-matched study in China. We will use conditional logistic regression model combined with distributed lag non-linear model to evaluate the effect of heat exposure on the different subtypes of PTB. Additionally, we will evaluate the effects of regional differences, and then use meta-analysis and meta-regression to estimate the pooled effects and modification of county-level factors. Moreover, we will evaluate the combined effects of extreme heat and air pollution using the relative excess risk due to their interactions. In the second stage, we aim to elucidate the potential mechanisms by which heat exposure leads to different types of PTB using a prospective cohort in Guangzhou. We will detect window-specific indicators of oxidative stress, inflammation, endothelial injury and hormones related to labor for each women, collect information on reproductive tract infection and gestational hypertension, and then apply structural equation model to build 3 hypothesis pathways as follow: (1) “heat exposure - oxidative stress and inflammation - endothelial injury - M-PTB”; (2) “heat exposure - reproductive tract infections/ reproductive tract infections and acute effects of heat in the third trimester - PROM-PTB” ; (3) “heat exposure - oxidative stress and inflammation - hormones associated with pregnancy- S-PTB”, to confirm the role of oxidative stress and inflammation, endothelial injury, infection, as well as hormones in the association of maternal heat exposure and PTB. This study will lay a solid foundation for strengthening cross-cutting and multi-disciplinary research in the field of meteorology, environment, climate change and public health.